Abstract: SA-PO338

Kidney Injury Induces HER3 Pathway Activation

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

  • Seva Pessoa, Bruno, Washington University St Louis, St. Louis, Missouri, United States
  • Kefalogianni, Eirini, Washington University School of Medicine, St. Louis, Missouri, United States
  • Herrlich, Andreas, Washington University in St. Louis, St. Louis, Missouri, United States
Background

Activation of epidermal growth factor receptor (EGFR or HER1) by specific soluble HER1 ligands drives injury-induced kidney fibrosis, and HER1 inhibition or deletion significantly protects against these effects. Another member of the HER family, HER3 has also been linked to fibrosis in lung and liver. HER1 function requires dimerization either with itself or with other HER receptors (HER2, HER3 or HER4). Whether HER3 and its ligands, soluble NRG1 and NRG2, are involved in injury-induced fibrosis and whether it acts in concert with HER1 or independently is unknown.

Methods

We performed bilateral ischemia-reperfusion injury (IRI) (30min of ischemia) or unilateral-ureteral-obstruction (UUO) (7 days) in wild-type mice. HER2, HER3, HER4 activation and their respective ligands were analyzed in mouse kidney samples by qPCR, Western blot and Immunofluorescence. Human biopsies were analyzed by Immunofluorescence.

Results

We show that kidney injury by IRI or UUO induces very significant transcriptional upregulation of HER3 and its ligands pro-NRG1 and pro-NRG2. Moreover, production of soluble active NRG1 was induced by IRI and HER3 phosphorylation could be detected in tubular cells and glomeruli. Similarly, fibrotic chronic kidney disease (CKD) biopsies also showed strong HER3 phosphorylation in tubular and glomerular compartments, suggesting that HER3 has an important function in these cellular compartments in mice and humans. To further study the HER3 pathway, we generated and validated proximal tubular- or podocyte-specific HER3 KO mice to test the role of HER3 in mouse models of kidney disease.

Conclusion

NRG1/HER3 pathway is activated by severe pro-fibrotic kidney injury, suggesting a potential role for NRG1/HER3 in this process.

Funding

  • NIDDK Support